Suspension aerosol formulations of pharmaceutical products

ABSTRACT

Pharmaceutical preparations for producing powder aerosols using propellant gases which use TG 227, and possibly also TG 11, TG 12, TGH 114, propane, butane, pentane or DME.

[0001] The invention relates to new propellent gases which contain as atypical ingredient 1,1,1,2,3,3,3-heptafluoropropane (TG 227), the use ofthese propellent gases in pharmaceutical preparations suitable forproducing aerosols, and these pharmaceutical preparations themselves.

[0002] Aerosols of powdered (micronised) drugs are used widely intherapy, e.g. in the treatment of obstructive diseases of therespiratory tract. If such aerosols are not produced by atomising thepharmaceutical powder or by spraying solutions, suspensions of the drugsin liquefied propellent gases are used. The latter consist primarily ofmixtures of TG 11 (trichlorofluoromethane), TG 12(dichlorodifluoromethane) and TG 114(1,2-dichloro-1,1,2,2-tetrafluoroethane), optionally with the additionof lower alkanes such as butane or pentane, or with the addition of DME(dimethylether). Mixtures of this kind are known for example from GermanPatent 1178975.

[0003] Owing to their harmful effect on the earth's atmosphere(destruction of the ozone layer, Greenhouse effect) the use ofchlorofluorocarbons has become a problem, with the result that thesearch is on for other propellent gases or propellent gas mixtures whichdo not have the above-mentioned harmful effects or, at least, have themto a lesser degree.

[0004] However, this search has come up against major problems, sincepropellent gases for therapeutic use have to satisfy numerous criteriawhich cannot easily be reconciled, e.g. in terms of toxicity, stability,vapour pressure, density and solubility characteristics.

[0005] As has now been found, TG 227 (1,1,1,2,3,3,3-heptafluoropropane,optionally in admixture with one of more propellent gases from the groupcomprising TG 11 (trichlorofluoromethane), TG 12(dichlorodifluoromethane), TG 114(1,2-dichloro-1,1,2,2-tetrafluoroethane), propane, butane, pentane andDME (dimethylether) is particularly suitable for use in therapeuticpreparations.

[0006] The compounds to be used in addition to TG 227 are added if theproperties of the propellent gas are to be modified, e.g. if theliquefied propellent gas is to have a different density, differentpressure or different solubility characteristics. Pharmaceuticalpreparations based on the propellent gas contain an active substance infinely divided form, usually as a suspension, and generally also containsurface-active substances, e.g. a phospholipid (such as lecithin), anester of a polyalcohol (such as sorbitol) with higher saturated orunsaturated fatty acids (e.g. stearic, palmitic or oleic acid), such assorbitan trioleate, or a polyethoxysorbitan ester of a higher,preferably unsaturated fatty acid. The adjuvant may be present in themixture in dissolved or undissolved form. In some cases, the suspensionsproduced with the new propellent gas have a tendency to separate out.However, it has been found that the separated suspensions can easily beuniformly distributed again in the suspension medium simply by shaking.

[0007] The ratios of quantities of the individual ingredients of thepropellent gas mixture may be varied within wide limits. The proportion(in percent by weight) is 10 to 100% in the case of TG 227. The mixturemay also contain up to 50% propane and/or butane and/or pentane and/orDME and/or TG 11 and/or TG 12 and/or TG 114. Within the limits specifiedthe ingredients are chosen to add up to 100%. Propellent gas mixtureswhich contain 30 to 100% TG 227 are preferred.

[0008] The proportion of suspended drug in the finished preparation isbetween 0.001 and 5%, preferably between 0.005 and 3%, more particularlybetween 0.01 and 2%. The surface-active substances are added in amountsof from 0.01 to 10%, preferably 0.05 to 5%, more particularly 0.1 to 3%(here, as in the case of the pharmaceutical substances, the percentageby weight of the finished preparation is given). The pharmaceuticalsubstances used in the new preparations may be any of the substancessuitable for use by inhalation or possibly for intranasaladministration. They include, therefore, in particular betamimetics,anticholinergics, steroids, antiallergics, PAF-antagonists andcombinations of these active substances.

[0009] The following are given as specific examples:

[0010] Examples of betamimetics:

[0011] Bambuterol

[0012] Bitolterol

[0013] Carbuterol

[0014] Clenbuterol

[0015] Fenoterol

[0016] Hexoprenalin

[0017] Ibuterol

[0018] Pirbuterol

[0019] Procaterol

[0020] Reproterol

[0021] Salbutamol

[0022] Salmeterol

[0023] Sulfonterol

[0024] Terbutalin

[0025] Tulobuterol

[0026]1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol

[0027]erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one

[0028]1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol

[0029]1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol.

[0030] Examples of anticholinergics:

[0031] Ipratropium bromide

[0032] Oxitropium bromide

[0033] Trospium chloride

[0034] Benzilic acid-N-β-fluoroethylnortropine ester methobromide

[0035] Examples of steroids:

[0036] Budesonide

[0037] Beclomethasone (or the 17, 21-dipropionate thereof)

[0038] Dexamethason-21-isonicotinate

[0039] Flunisolide

[0040] Examples of antiallergics:

[0041] Disodium cromoglycate

[0042] Nedocromil

[0043] Examples of PAF-antagonists:

[0044] WEB 2086

[0045] WEB 2170

[0046] WEB 2347

[0047] The active substances may also be combined, e.g. betamimeticsplus anticholinergics or betamimetics plus antiallergics.

[0048] Examples of preparations according to the invention (amountsgiven in percent by weight): 1) 0.10% Oxitropium bromide 2) 0.3%Fenoterol 0.01% Soya lecithin 0.1% Soya lecithin 4.0% Pentane 10.0%Pentane 95.89% TG 227 70.0% TG 227 19.6% TG 134a 3) 0.1% Ipratropiumbromide 4) 0.3% Fenoterol 0.1% soya lecithin 0.1% Soya lecithin 20.0%Pentane 30.0% TG 11 20.0% Butane 69.6% TG 227 49.8% TG 11 5) 1.5%Disodium 6) 0.3% Salbutamol cromoglicate 0.2% Span 85 0.1% Tween 2020.0% Pentane 98.4% TG 227 60.0% TG 227 1.4% Butane 19.5% TG 12 7) 0.15%Fenoterol 8) 0.1% Ipratropium- 0.06% Ipratropium- bromide bromide 0.1%Soya lecithin 0.10% Soya lecithin 15.3% Propane 40.00% TG 11 30.5% TG 1119.69% Propane 54.0% TG 227 40.00% TG 227

1. Propellent gases characterised in that they contain TG 227,optionally in admixture with one of more propellent gases from the groupcomprising TG 11, TG 12, TG 114, propane, butane, pentane and DME. 2.Propellent gases according to claim 1, characterised in that theyadditionally contain at least one surface-active substance. 3.Propellent gases according to claim 2, characterised in that thesurface-active substance is a phospholipid, a sorbitan ester with ahigher saturated or unsaturated fatty acid or a polyethoxysorbitan esterof a higher, preferably unsaturated fatty acid.
 4. Propellent gasesaccording to claim 2, characterised in that the surface-active substanceis a lecithin, a polyethoxyethylenesorbitan oleate or sorbitantrioleate.
 5. Pharmaceutical preparations for producing powder aerosolsbased on propellent gases according to claim 1, 2, 3 or 4, characterisedin that they contain as active substance a betamimetic, ananticholinergic, a steroid, an antiallergic or a PAF-antagonist or acombination of such compounds.
 6. Pharmaceutical preparations accordingto claim 5, characterised in that the betamimetic used is: BambuterolBitolterol Carbuterol Clenbuterol Fenoterol Hexoprenalin IbuterolPirbuterol Procaterol Reproterol Salbutamol Salmeterol SulfonterolTerbutalin Tulobuterol1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanolerythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanolthe anticholinergic used is: Ipratropium bromide Oxitropium bromideTrospium chloride Benzilic acid-N-β-fluoroethylnortropine estermethobromide the steroid used is: Budesonide Beclomethasone (or the 17,21-dipropionate thereof) Dexamethason-21-isonicotinate Flunisolide Theantiallergic agent is: Disodium cromoglycate Nedocromil ThePAF-antagonist is: WEB 2086 WEB 2170 WEB
 2347. 7. Pharmaceuticalpreparations according to claim 5, characterised in that the combinationof the active substances comprises one of the betamimetics specified inclaim 6 and one of the anticholinergics specified in claim
 6. 8.Pharmaceutical preparation according to claim 5, characterised in thatthe combination of the active substances comprises one of thebetamimetics specified in claim 6 and disodium chromoglycate. 9.Pharmaceutical preparation according to claim 5, characterised in thatthe combination of the active substances contains one of thebetamimetics specified in claim 6 and one of the PAF-antagonistsspecified in claim
 6. 10. Pharmaceutical preparation according to claim5, characterised in that the combination of the active substancescomprises disodium chromoglycate and one of the PAF-antagonistsspecified in claim
 6. 11. Process for preparing pharmaceuticalpreparations according to claims 5 to 10, characterised in thatpharmaceutically active substances micronised by conventional methodsare suspended in a liquefied propellent gas mixture according to claim1, 2, 3 or 4, optionally with the addition of surface-active substances.